Efforts to develop a gonococcal vaccine have continued for over three decades without notable progress. While the significant sequelae of infection in females and solid evidence that concurrent GC infection can enhance HIV transmission have spurred these investigations, this goal has become more urgent given the recent increase in GC antibiotic resistance, especially to ceftriaxone. Two major issues associated with this absence of success have been 1) the lack of an animal model that appreciates the human specificity of gonococcal adhesins and other virulence factors, and 2) the lack of correlates of immunity that can inform vaccine design. The overall objective of this proposal is to evaluate potential gonococcal vaccine candidates in a recently developed GC vaginal infection model utilizing humanized transgenic mice termed NeMo-8. The aims of this grant are to 1) Evaluate the immune response to vaginal gonococcal infection of the humanized TG mice, 2) Determine if infection with live organisms or immunization with killed organisms affords any protection in this mouse model, and 3) Evaluate the efficacy of gonococcal vaccine candidates, including gonococcal porin, gonococcal outer membrane vesicles, and other outer membrane components defined by Novartis Vaccines (see letter). If the aims are fulfilled, a new model for gonococcal vaccine evaluation will be established, correlates of gonococcal immunity will be discerned, and the relative utility of gonococcal vaccine candidates will be determined in order to prioritize and guide their future development towards their ultimate use in humans.